Solid tumors are the leading cause of death attributable to cancers worldwide. Conventional methods of treating cancer include surgical treatments, the administration of chemotherapeutic agents, and recently immune based treatments, which typically involve the administration of an antibody or antibody fragment. Although some encouraging results are being reported with the latter, an effective, life-prolonging treatment or a cure is not yet available for most cancers.
Surgical treatments are generally only successful if the cancer is detected at an early stage, i.e., before the cancer has infiltrated major organs. Chemotherapeutic treatments available today are also of limited usefulness because of their non-selective killing and/or toxicity to most cell types. Also, many tumor cells eventually become resistant against the chemotherapeutic agent, thus requiring treatment of such resistant tumors with new agents. Immune based treatments are also subject to numerous problems including difficulty in targeting antibodies to desired sites, e.g., solid tumors, and host immune reactions to the administered antibody.
The usage of small molecules for the prevention and treatment of cancer has also been reported. Antiestrogens and antiandrogens for the treatment/prevention of breast and prostate cancer, respectively, are excellent examples of a class of small molecule ligands that function via nuclear receptor signaling pathways. Another class of promising small molecule anti-cancer agents appears to be protein kinase inhibitors. Both classes of compounds are heterocyclic molecules in the 300 to 600 molecular weight range. Certain small molecules that are in some ways structurally related to the compounds of the instant invention, and disclosed to be potentially useful in the treatment of certain cancers were disclosed in U.S. patent application Ser. No. 09/655,460 filed Aug. 31, 2000. Certain other small molecules effective for the treatment of diabetes, that are in some ways structurally related to the compounds of the instant invention were disclosed in U.S. patent application Ser. No. 09/652,810 filed Aug. 31, 2000. The disclosures of both the above-described U.S. patent applications are hereby incorporated herein by this reference, for both their chemical structural disclosures, and their teachings of the biological activities of those compounds, and methods for their use as pharmaceutical compositions.
The present invention relates to a series of heterocyclic compounds that show unexpected, potent anti-cancer activity in vitro and in vivo. These compounds are useful in the treatment of diseases of uncontrolled proliferation, such as cancer and precancerous conditions, in mammals. This invention also relates to a method of using such compounds in the treatment of diseases of uncontrolled proliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing compounds disclosed herein.